Oral solid cannabinoid oil composition for treating gastrointestinal disorders

ABSTRACT

Cannabinoid oil compositions may be used to treat gastrointestinal disorders. An example of the composition is an oral multiparticulate dosage form including a plurality of individual particulates including a solid core with an effective amount of cannabinoid oil bound in microcrystalline cellulose therein and an enteric coating over the solid core.

CROSS-REFERENCE TO RELATED APPLICATION

This claims the benefit of priority from U.S. Application No.62/958,392, filed Jan. 8, 2020, which is incorporated by reference inits entirety.

FIELD

This relates to the field of cannabinoid oil formulations and, moreparticularly, to cannabinoid oil formulations for treatinggastrointestinal disorders.

BACKGROUND

Cannabinoids are a class of compounds that act on cannabinoid receptorsin the body. Cannabinoid receptors are part of the body'sendocannabinoid system, which is composed of the cannabinoid receptors,endogenous cannabinoids called endocannabinoids, and chemicals used tosynthesize endocannabinoids. Endocannabinoids are neurotransmitters.

Cannabinoids have been studied for decades for their therapeutic effectsand some have been approved as drugs. EPIDIOLEX® is an oral solutioncontaining cannabidiol “CBD” for treating certain forms of epilepsy.SATIVEX® is an aerosol spray containing CBD and tetrahydrocannabinol“THC” for treating pain in patients with multiple sclerosis. MARINOL®,which contains a synthetic form of THC called dronabinol, is used totreat emesis associated with chemotherapy and AIDS-related anorexiarelated to weight loss.

Others have reported that cannabinoids may be used to treatgastrointestinal disorder symptoms because cannabinoid receptors CB1 andCB2 are located in the gastrointestinal tract. According to Gyires andZádori in “Role of Cannabinoids in Gastrointestinal Mucosal Defense andInflammation,” Current Neuropharmacology, Vol. 14, pgs. 935-951 (2016),there are numerous studies reporting therapeutic benefits ofcannabinoids against inflammatory bowel diseases, including Crohn'sdisease and ulcerative colitis, for example.

BRIEF SUMMARY

The problem with treating gastrointestinal disorders using cannabinoidsis that there is a shortage of oral cannabinoid dosage forms that canspecifically target areas of inflammation in the gastrointestinal tractand can bypass CB2 receptors in the stomach. This problem is solvedusing an oral pharmaceutical dosage form comprising a solid matrix ofmicrocrystalline cellulose and a cannabinoid oil.

An example of such a composition includes an oral multiparticulatedosage form including a plurality of individual particulates. Theindividual particulates have a solid core including an effective amountof cannabinoid oil bound in microcrystalline cellulose and an entericcoating over the solid core. The composition may further include one ormore of the following additional features.

The individual particulates may be spheroidal, have an average diameterof 0.5 mm to 1.7 mm, and further include an enteric coating material anda disintegrant combination that cause the individual particulates torelease most of the cannabinoid oil in a subject's duodenum for treatinginflammation of the duodenum.

The individual particulates may be spheroidal, have an average diameterof 0.5 to 1.7 mm, and may be configured to release most of thecannabinoid oil in the jejunum for treating inflammation of the jejunum.

The individual particulates may be spheroidal, have an average diameterof 0.5 to 1.7 mm, and may be configured to release most of thecannabinoid oil in the ileum for treating inflammation of the ileum.

The individual particulates may be spheroidal, have an average diameterof 1.8 to 3 mm, and the dosage form may be configured to release thecannabinoid oil for at least 6 hours throughout the intestines.

The cannabinoid oil may be bound in microcrystalline cellulose by beingstored within microcrystalline cellulose's fibrous network.

The cannabinoid oil bound in microcrystalline cellulose may besubstantially dry.

A ratio of the cannabinoid oil to MCC may be 0.5:1 to 1.5:1.

The individual particulates may further include 10% w/w to 50% w/wcannabinoid oil, 40% w/w to 75% w/w microcrystalline cellulose, 2% w/wto 10% w/w methyl cellulose, and 2% w/w to 35% w/w enteric coating.

The cannabinoid oil may include CBD oil.

The composition may include any combination of these features.

An example of a processing method includes wet granulatingmicrocrystalline cellulose and a cannabinoid oil together forming asolid matrix in which the cannabinoid oil is bound in the MCC andcombining the solid matrix with at least one pharmaceutical excipient toform an oral pharmaceutical dosage form. The method may further includeone or more of the following additional features.

Wet granulating may be performed in a high shear mixer above roomtemperature for 10 minutes to 20 minutes.

The oral pharmaceutical dosage form may be a multiparticulate dosageform including a plurality of individual spheroidal particulates havingan average diameter of 0.5 mm to 3 mm.

The cannabinoid oil may be bound in microcrystalline cellulose by beingstored within microcrystalline cellulose's fibrous network.

The cannabinoid oil bound in microcrystalline cellulose may besubstantially dry.

A ratio of the cannabinoid oil to MCC may be 0.5:1 to 1.5:1.

The oral pharmaceutical dosage form may include 10% w/w to 50% w/wcannabinoid oil, 40% w/w to 75% w/w microcrystalline cellulose, 2% w/wto 10% w/w methyl cellulose, and 2% w/w to 35% w/w enteric coating.

The cannabinoid oil may include CBD oil.

The method may further include any combination of the these features.

An example of a therapeutic method includes treating a gastrointestinaldisorder by administering an effective amount of the composition aboveto a subject having a gastrointestinal disorder. The method may furtherinclude one or more of the following additional features.

The individual particulates may be spheroidal, have an average diameterof 0.5 mm to 1.7 mm, and further comprise an enteric coating materialand a disintegrant combination that cause the individual particulates torelease most of the cannabinoid oil in a subject's duodenum for treatinggastroparesis and/or functional dyspepsia.

The individual particulates may be spheroidal, have an average diameterof 0.5 to 1.7 mm, and may be configured to release most of thecannabinoid oil in the jejunum for treating inflammatory bowel syndrome.

The individual particulates may be spheroidal, have an average diameterof 0.5 to 1.7 mm, and may be configured to release most of thecannabinoid oil in the ileum for treating Crohn's disease, ileitis,and/or ulcerative colitis.

The individual particulates may be spheroidal, have an average diameterof 1.8 to 3 mm, and the dosage form may be configured to release thecannabinoid oil for at least 6 hours throughout the intestines.

The cannabinoid oil may be bound in microcrystalline cellulose by beingstored within microcrystalline cellulose's fibrous network.

The cannabinoid oil bound in microcrystalline cellulose may besubstantially dry.

A ratio of the cannabinoid oil to MCC may be 0.5:1 to 1.5:1.

The individual particulates may further include 10% w/w to 50% w/wcannabinoid oil, 40% w/w to 75% w/w microcrystalline cellulose, 2% w/wto 10% w/w methyl cellulose, and 2% w/w to 35% w/w enteric coating.

The cannabinoid oil may include CBD oil.

The method may further include any combination of the these features.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a schematic of a human's lower gastrointestinal tract,including the stomach, small intestine, and colon.

FIG. 2 is a photograph of a solid matrix formed from wet granulating MCCand CBD oil.

DETAILED DESCRIPTION OF EXAMPLE EMBODIMENTS

The cannabinoid composition described here may be used to treat manydifferent human or animal ailments, but some examples are particularlyadvantageous for treating gastrointestinal disorder symptoms such asthose associated with functional gastrointestinal disorders includingirritable bowel syndrome (“IBS”), functional dyspepsia (“FD”),gastroparesis, diverticulosis and constipation; and those associatedwith inflammatory bowel diseases (“IBD”), including Crohn's disease,ileitis, and ulcerative colitis. Such examples of the composition areformulated to relieve symptoms of one or more of these problems bytargeting the specific site of inflammation associated with thedisorder.

Pertinent parts of the gastrointestinal tract 10 are now generallydescribed by referring to FIG. 1 . When a subject ingests an oral dosageform, it travels to the stomach 12 where digestion takes place. If thedosage form is enteric coated, it will not release its contents into thestomach because the enteric coating will not dissolve at the stomach'spH, which is about 1 to 3.

From the stomach 12, the dosage form passes through the pylorus valve 14into the duodenum 16, which is the upper (first) section of the smallintestine 18. The pH in the duodenum 16 is about 4 to about 6. Once itleaves the duodenum 16, it enters the jejunum 20 where the pH is about5.5 to about 6.5. After the jejunum 20, it enters the ileum 22 where thepH is about 6.5 to about 7.4. The cecum and colon 24, or largeintestine, is past the ileum 22. The pH in the cecum drops down to about5.7 but gradually increases to a pH of about 7. The pH of varioussections of the GI tract are reported by Lalezari in Annals ofGastroenterology, Vol. 25, pgs. 1-5 (2012), by Evans, et al. in Gut,Vol. 29, pgs. 1035-41 (1988) and by Dressman, et al. in PharmaceuticalResearch, Vol. 7(7), pgs. 756-761 (1990).

IBS symptoms originate in the jejunum according to Martinez, et al. inGut, Vol. 62, pgs. 1160-68 (2013).

The duodenum is the site of inflammation for functional dyspepsiaaccording to Micklefield, et al., Phytotherapy Research, Vol. 14, pgs.20-23, (2000).

For Crohn's disease and ileitis, the inflammation is mostly localized inthe ileum as reported by DiLauro et al. in Curr. Gastroenterol. Rep.,Vol. 12(4), pgs. 249-58 (2010).

Some examples of the composition are designed to minimize the foodaffect, which is the degree to which food enhances or inhibits theuptake of a cannabinoid in the body.

An example of composition includes a solid matrix including acannabinoid oil and microcrystalline cellulose (“MCC”). The solid matrixis a combination of at least these two components in a solid form wherethe cannabinoid oil component has been taken up by the MCC and is storedwithin MCC's fibrous network. The solid matrix may be produced by a wetgranulation process in which the cannabinoid oil and MCC are granulatedtogether. The wet granulation process may be performed using aconventional pharmaceutical mechanical wet granulation technique such ashigh shear granulation, mortar and pestle, and fluidized bedgranulation, among other possible examples.

During the granulation process, the MCC forms a solid matrix with thecannabinoid oil. The MCC fiber network forms a porous scaffolding towhich the cannabinoid oil binds. The resulting solid matrix from wetgranulation is composed of solid micrometer and millimeter sizedgranules that are substantially dry or not oily in texture. By beingsubstantially dry, the granules have a powder texture. An example of thesolid matrix is shown in FIG. 2 .

The fact that MCC and cannabinoid oil can be combined to form such asolid matrix is surprising. MCC is known to be a hydrophilic polymerthat will absorb water, but, because cannabinoid oils are substantiallywater insoluble, one would not expect MCC to absorb the cannabinoid oilvery well.

It is surprising that MCC can store a relatively large amount ofcannabinoid oil. In certain examples, the ratio of MCC to cannabinoidoil is from 1:4 to 4:1 or 0.5:1 to 1.5:1. In a particular example, thecannabinoid oil to MCC ratio in the solid matrix is about 1:1. Thisunique and newly discovered property allows for high dose loading of thecannabinoid oil in the dosage form.

MCC is a conventional pharmaceutical excipient that is widely used as adisintegrant in solid oral dosage forms. In examples of the presentcomposition, however, the MCC functions as a release-controlling polymerand provides for a sustained release of cannabinoid(s) from thecannabinoid oil. The MCC may gradually release cannabinoid oil into thegastrointestinal tract rather than quickly dumping the entire dose atone site. Accordingly, the MCC may help overcome effects of dosedumping.

The cannabinoid oil is composed of at least one cannabinoid dissolved inan oil carrier. In certain examples, the cannabinoid oil is prepared bydissolving a substantially pure cannabinoid in a pharmaceuticallyacceptable medium chain triglyceride oil such as vegetable oil, sesameoil, coconut oil, or the like. In other examples the cannabinoid oil isa plant extract obtained from a Cannabis plant such as CBD oil, Cannabisoil, hemp extract, hemp oil, or the like. Because such plant extractsare commercially available, methods of making a plant extractcannabinoid oil are not described in detail.

There are many cannabinoid compounds that the cannabinoid oil mayinclude, including one or more of tetrahydrocannabinol (“THC”),cannabidiol (“CBD”), tetrahydrocannabinolic acid (“THCA”), cannabidiolicacid (“CBDA”), cannabinol (“CBN”), cannabigerol (“CBG”), cannabichromene(“CBC”), cannabicyclol (“CBL”), cannabivarin (“CBV”),tetrahydrocannabivarin (“THCV”), cannabidivarin (“CBDV”),cannabichromevarin (“CBCV”), cannabigerovarin (“CBGV”), cannabigerolmonomethyl ether (“CBGM”), cannabielsoin (“CBE”), and cannabicitran(“CBT”).

If it is undesirable to produce a psychoactive effect in the subjectbeing treated, cannabinoid oil predominant in CBD, CBG, and/or CBC maybe used. In a particular example, CBD oil is used as the cannabinoidoil. The predominant cannabinoid in CBD oil is CBD, but CBD oil may alsocontain lesser amounts of one or more other cannabinoids.

Some examples of the solid matrix may further include a hydrogel formingpolymer such as a cellulose-based, starch-based, and/or povidone-basedmaterial. It is to be understood that “cellulose-based,” “starch-based”binders, and “povidone-based” binders includes cellulose, starch, andpovidone derivatives. When mixed with water, these materials swells toform a hydrophilic hydrogel matrix. Examples of cellulose-basedhydrogel-forming materials include methylcellulose based polymers,including, for example, methylcellulose and hydroxypropylmethylcellulose. Using a hydrogel forming polymer in the solid matrixmay be useful to modulate the rate of release of cannabinoid(s) from thecannabinoid oil from the solid matrix in the gastrointestinal tract.

The solid matrix may be combined with pharmaceutical excipients to formorally ingestible solid pharmaceutical dosage forms such as powders,granules, pills (tablets, capsules, caplets), multiparticulates, andsachets. Such excipients may include pharmaceutically acceptablefillers, stabilizers, binders, surfactants, processing aids, and/ordisintegrants. By way of example only, examples of materials forperforming these functions are provided.

Examples of fillers include dibasic calcium phosphate, extragranular MCCoutside the solid matrix, lactose, sucrose, and/or anotherpharmaceutically acceptable filler.

Examples of binders include cellulosic water soluble polymers such asmethyl cellulose, starch, hydroxypropyl cellulose, gelatin,polyvinylpyrrolidone, polyethylene glycol, hydroxypropyl methylcelluloseand/or another pharmaceutically acceptable binder. The binder, in suchcases, is extragranular, meaning it is outside the solid matrix.

Processing aids include pharmaceutically acceptable processing aids forimproving the flowability of the materials during processing. Examplesof processing aids include colloidal silicon dioxide, talc, magnesiumstearate, stearin, and/or another pharmaceutically acceptable processingaid.

Examples of disintegrants include, croscarmellose sodium,polyvinylpyrrolidone (crospovidone) sodium starch glycolate, and/oranother pharmaceutically acceptable processing aid.

If the dosage form is a tablet or the like, the solid matrix may becombined with the desired excipients to form the tablet by using aconventional tableting technique such as compression, for example.

In certain examples the dosage form is an oral multiparticulate dosageform. In a multiparticulate dosage form there are a plurality ofindividual particulates that are preferably spheroidal in shape and aresized to fit through the pylorus valve irrespective of the gastric phaseof digestion. The diameter of each particulate is preferably in therange of about 0.1 mm to about 3 mm, about 1 mm to about 2.5 mm, about0.1 to about 2 mm, 0.5 mm to 1.5 mm, 0.5 mm to 1.7 mm, 1.8 mm to 2.1 mm,1.8 mm to 3 mm, 0.5 mm to 2.1 mm, 0.5 mm to 3 mm, or less than about 2mm. Particulates of this diameter pass through pylorus valve when it isrelaxed, meaning they do not remain in the stomach as long assingle-unit capsules. Typically, a significant number of particulateswill have passed through the stomach within about thirty minutes afteringestion. Such a multiparticulate dosage form may help minimize thefood affect.

An example of a method of making the composition includes wetgranulating microcrystalline cellulose and a cannabinoid oil togetherforming a solid matrix in which the cannabinoid oil is bound in the MCC.The solid matrix is combined the solid matrix with at least onepharmaceutical excipient to form an oral pharmaceutical dosage form.

Relative to many types of conventional wet granulation, forming the soldmatrix may sometimes require increased mechanical energy to get thecannabinoid oil to bind within the MCC fibrous network. In certainexamples, the wet granulating step is performed in a high shear mixer atelevated temperature for a time sufficient to make the sold matrix havea substantially dry and non-oily texture. The elevated temperature maybe just above room temperature or from 26 degrees C. to 50 degrees C.,for example. The time may be 10 minutes to 20 minutes or about 15minutes, for example.

The individual spheroidal particulates may be prepared by an extrusionspheronization process. A core may be prepared by wet granulating thesolid matrix and core excipients into a wet mass, extruding the wet massto form an extrudate, cutting the extrudate into a plurality of corepieces, and spheronizing the core pieces. The spheronized core piecesare then dried in a dryer such as a fluid bed dryer to remove most ofthe water. If desired, the dried spheronized cores are then sieved toseparate cores of different sizes.

In some examples, the dosage form is formulated to substantially preventreleasing the cannabinoid(s) of the cannabinoid oil in the stomach byincluding an enteric coating. The enteric coating material may be chosento dissolve at a specific pH within the gastrointestinal tract,approximately corresponding to the pH at the site of inflammation causedby the disorder being treated. Accordingly, if a subject has beendiagnosed with a particular gastrointestinal disorder and the site ofinflammation for that disorder is known, one may choose an entericcoating that dissolves within the pH range where the site ofinflammation is located.

Table 1 lists examples of some commercially available enteric coatingmaterials and the pH at which they dissolve. The list of possibleenteric coating materials is not limited only to these. Examples ofother enteric coating materials include, for example, other methacrylicacid copolymers, cellulose acetate phthalate, polyvinyl acetatephthalate, and ethyl cellulose/sodium alginate coatings such asNUTRATERIC® (Colorcon, Inc).

TABLE 1 Examples of Enteric Coating Materials Dissolution Brand CompanyGeneric Name pH KOLLICOAT ® BASF Methacrylic acid-ethyl 5.5 and aboveMAE 30DP Corp. acrylate copolymer EUDRAGIT ® Evonik Methacryliccopolymer   7 and above FS 30D Industries with carboxylic acid AGfunctional groups EUDRAGIT ® Evonik Anionic copolymers   7 and aboveS100 Industries based on methacrylic AG acid and methyl methacrylate.AQOAT ® Shin Etsu Hypromellose acetate   6 and above AS-HF Chemicalsuccinate Co., Ltd

Some examples of the dosage form delay releasing the cannabinoid(s) fromthe cannabinoid oil until the dosage form reaches the site ofinflammation, but once the dosage form arrives there and the entericcoating dissolves, the MCC matrix sustains the release of cannabinoid(s)of the cannabinoid oil at the site of inflammation.

In certain examples, the individual particulates of the multiparticulatedosage form include 10% w/w to 50% w/w cannabinoid oil, 40% w/w to 75%w/w microcrystalline cellulose, 2% w/w to 10% w/w binder such asmethylcellulose or the like, and 2% w/w to 35% w/w enteric coating.

The following cannabinoid release profiles are provided for illustrationonly. For treating IBS, the dosage form may release cannabinoid(s) fromthe dosage form for about 2.5 to about 3 hours. For treating functionaldyspepsia and/or gastroparesis, the dosage form may releasecannabinoid(s) from the dosage form for about 1.5 hours. For treatingCrohn's disease, each the dosage form may release cannabinoid(s) fromthe dosage form for about 4.5 to about 5 hours. For treating ulcerativecolitis or diverticulitis, the dosage form may release cannabinoid(s)from the cannabinoid oil from about 4 hours to about 72 hours.

The multiparticulate dosage form may also provide a sustained release ofcannabinoid(s) from the cannabinoid oil because the particulates do notall reach the site of inflammation at the same time. This means thatthere will be a somewhat continuous flow of particulates to the site ofinflammation as the individual particulates pass through the intestinesand the content in the stomach gradually passes thru the pyloric valveand enters the small intestine. An estimated time it takes theparticulates to pass through the small intestine is about 3 to about 6hours, including about 1 hour to pass through the duodenum and about 1.5hours to pass through the jejunum plus about 2 hours to pass through theileum. After passing through the small intestine, the time it takes theparticulates to pass through the large intestine (colon) is about 4hours to about 72 hours.

For the multiparticulate dosage form, the enteric coating may be appliedover each core. For a pill dosage form, the enteric coating may beapplied over the pill. The enteric coating may be about 2% w/w to about35% w/w of the dosage form or about 3.5% w/w to about 50% w/w of thedosage form.

A particular example of an enteric coating material is a methacrylicacid based material such as a methacrylic acid based co-polymer,including a methacrylic acid/ethylacrylate co-polymer, an example ofwhich is KOLLICOAT® MAE 30 DP. These materials may be combined withother materials such as plasticizers for forming an enteric coatingsolution.

An example of an enteric coating solution may include about 5% w/w toabout 35% w/w water, 0.5% w/w to about 5% w/w plasticizer, about 0.05%w/w to about 5% w/w anti-adherent, and about 2% w/w to about 35% w/wmethacrylic acid copolymer. An example of a plasticizer is triethylcitrate and an example of an anti-adherent is PLASACRYL® T20 (EmersonResources, Inc.). PLASACRYL® T20 is an emulsion of anti-tacking agentand plasticizer and contains water, glyceryl monostearate, triethylcitrate and polysorbate 80.

The enteric coating may be applied to the dosage form by anyconventional enteric coating technique such as by spray coating, fluidbed coating, and the like.

Certain examples may include a subcoating over the core and between thecore and enteric coating. The subcoating may be about 3.5% w/w to about40% w/w of the individual enteric coated particulate. The subcoating maybe made of a pharmaceutically acceptable coating forming material suchas a gelatin, hydroxypropyl methylcellulose or the like. The subcoatingmay be applied to the dosage form by any conventional pharmaceuticalcoating technique such as by spray coating, fluid bed coating, and thelike.

The composition may be used to treat many different types ofgastrointestinal disorders by providing relief from inflammation. Theformulation can vary depending on the type of gastrointestinal disorderbeing treated.

The cannabinoid release profile in the body can be varied to treatdifferent gastrointestinal disorders by formulating it to release thecannabinoid(s) of the cannabinoid oil at the site of inflammation ingastrointestinal tract associated with the disorder being treated. Thisis accomplished by selecting an enteric coating that dissolves at aboutthe pH of the site of inflammation and by controlling the release rateof cannabinoid(s) from the cannabinoid oil at the site of inflammationusing different particulate diameters and/or a disintegrant.

To treat gastrointestinal disorder symptoms associated with inflammationof the jejunum, such as irritable bowel syndrome, the composition may beformulated to minimize the amount of cannabinoid(s) released into thestomach and colon, so that most of, or at least about 50% to about 75%of, the cannabinoid(s) is released in the small intestine, particularlythe jejunum. Preferably, 20% or less of the cannabinoid(s) is releasedinto the stomach and 20% or less of the cannabinoid(s) is released intothe colon. Also, the cannabinoid(s) is preferably gradually releasedover the course of about 2 to about 4 hours after the dosage form passesthe pylorus valve in order to deliver the cannabinoid(s) locally in thejejunum. This release profile treats IBS by treating gastrointestinalsymptoms associated with IBS. In such a composition, the averagediameter of the particulates may, for example, be 0.5 mm to 1.7 mm.

To treat gastrointestinal disorders associated with inflammation of theduodenum, such as functional dyspepsia and/or gastroparesis, the dosageform is formulated so that the cannabinoid(s) is substantially releasedin the duodenum after the dosage form passes through the stomach andpylorus valve over the course of about 0 to about 2 hours. This deliversthe cannabinoid(s) locally to the duodenum to substantially relieve thesymptoms associated with functional dyspepsia and gastroparesis, forexample. Preferably, 20% or less of the cannabinoid(s) is released inthe stomach and 20% or less of the cannabinoid(s) is released in thelater sections of the intestines, including the ileum, and colon. Toobtain an effective release of cannabinoid(s) from the cannabinoid oilinto the duodenum, the dosage form may include a disintegrant. Theamount of disintegrant, if used, may be about 1% w/w to 20% w/w of thedosage form. Use of a disintegrant is not necessary in every example. Insuch a composition, the average diameter of the particulates may, forexample, be 0.5 to 1.7 mm.

To treat gastrointestinal disorders associated with inflammation of theileum; such as inflammatory bowel diseases, including Crohn's disease,ileitis, and/or ulcerative colitis; the dosage form is formulated sothat the cannabinoid(s) is substantially released in the ileum after thedosage form passes through the stomach and pylorus valve over the courseof about 4 to about 6 hours. This delivers the cannabinoid(s) locally tothe ileum to substantially relieve the symptoms associated with suchdisorders. Preferably, 50% to 75% of the cannabinoid(s) is released inthe ileum. Preferably, greater than 70% of the cannabinoid(s) isreleased after the particulates reach the pH of the ileum. To obtain aneffective release of cannabinoid(s) from the cannabinoid oil into theileum. In such a composition, the average diameter of the particulatesmay, for example, be 0.5 to 1.7 mm.

In some cases it may be desirable to administer a dosage form that cancontinuously release the cannabinoid(s) more generally throughout theintestines to treat less acute inflammations. This may be achieved usingparticulates having an average diameter of about 1.8 to 3 mm. The largeraverage diameter ensures a slower and more sustained release ofcannabinoid(s) for at least 5 to 8 hours after administration.

A general method of treatment includes orally administering an effectiveamount of the pharmaceutical dosage form to a subject having agastrointestinal disorder. The dosage form may include any of thefeatures described above. Examples of gastrointestinal disordersinclude, but are not limited to inflammation of the duodenum,inflammation of the jejunum, inflammation of the ileum, IBS, FD,gastroparesis, Crohn's disease, ulcerative colitis, ileitis, andconstipation.

An exemplary method of treating inflammation of the jejunum, which maybe caused by irritable bowel syndrome, includes orally administering aneffective amount of the pharmaceutical dosage form to a subject havingthe inflammation of the jejunum. The dosage form may include any of thefeatures described above. The dosage form releases most of thecannabinoid(s) in the subject's jejunum. In some examples, the dosageform releases at least about 50% to about 75% of the cannabinoid(s) intothe jejunum.

An exemplary method of treating inflammation of the duodenum, which maybe caused by functional dyspepsia and/or gastroparesis, includes orallyadministering an effective amount of the dosage form to a subject havingthe inflammation of the duodenum. The dosage form may include any of thefeatures described above. The dosage form may release most of thecannabinoid(s) in the subject's duodenum. In some examples, the dosageform releases at least about 50% to about 75% of the cannabinoid(s) intothe duodenum.

An exemplary method of treating inflammation of the ileum, which may becaused by an inflammatory bowel disease such as Crohn's disease,ulcerative colitis, and ileitis; includes orally administering aneffective amount of the dosage form to a subject having the inflammationof the ileum. The dosage form may include any of the features describedabove. The dosage form may release most of the cannabinoid(s) in thesubject's ileum. In some examples, the dosage form releases at leastabout 50% to about 75% of the cannabinoid(s) into the ileum.

“Relief” that subjects obtain from the dosage form is a measurablequantity, not just a subjective determination, because relief fromgastrointestinal disorder symptoms may be quantified statistically usingconventional clinical protocols from a pool of subjects. These clinicalprotocols may include the use of the Gastrointestinal Symptom RatingScale (GSRS) or the Visual Analog Scale (VAS). Both of these scalesquantify a particular subject's symptoms based on the subject'sresponses to various questions pertaining to those symptoms. Byrecording GSRS and/or VAS data for a pool of subjects at various stagesof treatment with the treatment composition, one can statisticallymeasure how quickly the treatment composition relieves the subject'ssymptoms. An example of a suitable protocol for measuring “relief” usingthe VAS is reported by Hawker, et al. in Arthritis Care & Research, Vol.63 No. S11, pgs. S240-S252 (2011).

The dosage form includes an effective amount of the cannabinoid oil. Aneffective amount is an amount that is sufficient to affect a disease orcondition in the body. An effective amount of cannabinoid oil may be,for example: 0.01-5,000 mg, 0.01-1,000 mg, 0.01-500 mg, 0.01-200 mg,0.01-100 mg, 0.01 to 50 mg, 0.01-25 mg, 0.01-10 mg, or 0.01-5 mg. Theeffective amount can vary outside of these ranges as well. The weight inmg is often calibrated to the body weight of the subject in kg, thusthese example doses may also be written in terms of mg/kg of body weightper day.

In practice, the effective amount may vary depending on numerous factorsassociated with the subject, including age, weight, height, severity ofthe condition, administration technique, and other factors. Theeffective amount administered to a subject may be determined by medicalpersonnel taking into account the relevant circumstances.

The effective amount may be determined or predicted from empiricalevidence. Specific dosages may vary according to numerous factors andmay be initially determined on the basis of experimentation.

The dosage form may be administered as a single dose or as part of adosage regimen. For a dosage regimen, the therapeutically effectiveamount is adjustable dose to dose to provide a desired therapeuticresponse.

Multiple doses may be administered at a predetermined time interval andsubsequent doses may be proportionally reduced or increased, dependingon the situation.

The dosage form may be administered sporadically when needed fortreating inflammations of the gastrointestinal tract or may beadministered as part of a long term regimen for treatinggastrointestinal disorders. A treatment subject may be a human oranimal.

It should be understood that where this disclosure makes reference totreating a gastrointestinal disorder, that the terms “treat,”“treating,” or any other variation of the word “treat” includeprevention of, management of, and substantial symptom relief from thegastrointestinal disorder.

EXAMPLES

The following examples are provided to illustrate aspects of certainexamples of the composition. The scope of possible examples is notlimited to the details of these examples.

Example 1: Wet Granulation of MCC and CBD Oil

A solid matrix of MCC and CBD oil was prepared by mechanically wetgranulating about 2 mL of CBD oil with about 2 grams of MCC (MCC 102)for two minutes. The CBD oil was manufactured by SUNMED ORGANICINGREDIENTS™ and contained organic medium chain triglyceride oil, hempextract, organic flavoring, and plant-derived terpenes, with 500+ mg oftotal cannabinoids (CBD, CBG, CBC, CBN and CBD-V). The resulting wetgranulation had a substantially dry powder appearance and did not havean oily texture. This proves that CBD oil is capable of being bound inan MCC scaffolding even though MCC is a hydrophilic polymer. FIG. 2 is aphotograph of the wet granulation.

Example 2: Preparation of an Example Formulation

Spheroidal cores are prepared by blending 50 kg of microcrystallinecellulose, 5 kg methyl cellulose, and 50 kg CBD oil with water to form awet mass. The wet mass is granulated in a high shear granulator thenextruded and spheronized. The spheronized wet cores are dried in a fluidbed dryer to form uncoated dried cores. The drying temperature is about16 degrees C. The diameter of the uncoated dried cores is set byselecting by cutting the extrudate into appropriate size pieces prior tospheronization.

An enteric coating is applied to the uncoated dried cores using 31 kg ofa 20% w/w solution of KOLLICOAT® MAE 30 DP, PLASACRYL® T20, triethylcitrate, and water. The dry solids weight of KOLLICOAT® MAE 30 DP isabout 5 kg. The dry solids weight of triethyl citrate is about 0.3 kg.The dry solids weight of PLASACRYL® T20 is about 0.5 kg. The entericcoated cores are dried at about 40 degrees C. The enteric coatingprovides a weight gain to the cores of about 10% w/w.

If desired, the uncoated dried cores may optionally be subcoated with 37kg of a subcoating solution containing about 15% acid bone gelatin and85% USP water and dried. The subcoating provides a weight gain to thecores of about 10% w/w.

If desired, an optional finish coat may be applied over the entericcoat. The finish coat is 26 kg of a finish coat solution containingabout 10% w/w hydroxypropyl methylcellulose and 90% water. The finishcoated particulates are dried at about 40 degrees C. The finish coatprovides a weight gain to the enteric coated cores of about 2% w/w.

The finished particulates are loaded into gelatin capsules of thedesired size.

Example 3: Example Formulations

In a composition that may be useful for treating inflammation of thejejunum, a capsule of the multiparticulates includes 200 mg CBD oil, 200mg MCC, 20 mg methyl cellulose (binder), 20 mg gelatin (subcoat), 22 mgenteric coat. The particulate diameter is about 1.5 mm

In a composition that may be useful for treating inflammation of theduodenum, a capsule of the multiparticulate includes 200 mg CBD oil, 200mg MCC, 20 mg methyl cellulose, 50 mg croscarmellose sodium(disintegrant), 20 mg gelatin (subcoat), and 22 mg enteric coat. Theparticulate diameter is about 1.5 mm.

In a composition that may be useful for treating inflammation of theileum includes, a capsule of the multiparticulates includes 200 mg CBDoil, 200 mg MCC, 20 mg methyl cellulose (binder), 20 mg gelatin(subcoat), 22 mg enteric coat. The particulate diameter is about 1.5 mm.

In a sustained release composition for releasing the cannabinoid(s)throughout the intestines, a capsule of the multiparticulates includes200 mg CBD oil, 200 mg MCC, 20 mg methyl cellulose (binder), 20 mggelatin (subcoat), 22 mg enteric coat The particulate diameter is about2 mm.

This disclosure describes exemplary embodiments, but not all possibleembodiments of the compositions and methods. Where a particular featureis disclosed in the context of a particular example, that feature canalso be used, to the extent possible, in combination with and/or in thecontext of other examples. The compositions and methods may be embodiedin many different forms and should not be construed as limited to onlythe examples described here.

The compositions and methods are not limited to the details described inconnection with the example embodiments. There are numerous variationsand modification of the compositions and methods that may be madewithout departing from the scope of what is claimed.

That which is claimed is:
 1. A composition comprising: an oralmultiparticulate dosage form including a plurality of individualparticulates, wherein the individual particulates are spheroidal andcomprise: (a) a solid core including an effective amount of cannabinoidoil bound in microcrystalline cellulose (MCC) in a ratio of thecannabinoid oil to the MCC of 0.5:1 to 1.5:1; and (b) an enteric coatingover the solid core, wherein the individual particulates are selectedfrom the group consisting of: (i) the individual particulates have anaverage diameter of 0.5 mm to 1.7 mm and further comprise an entericcoating material and a disintegrant combination configured for theindividual particulates to release at least about 50% of the cannabinoidoil in a subject's duodenum for treating inflammation of the duodenum;(ii) the individual particulates have an average diameter of 0.5 to 1.7mm and are configured to release at least about 50% of the cannabinoidoil in a subject's jejunum for treating inflammation of the jejunum; and(iii) the individual particulates have an average diameter of 0.5 to 1.7mm and are configured to release at least about 50% of the cannabinoidoil in a subject's ileum for treating inflammation of the ileum, whereinthe individual particulates comprise 10% w/w to 50% w/w of thecannabinoid oil, 40% w/w to 75% w/w of the microcrystalline cellulose,2% w/w to 10% w/w methyl cellulose, and 2% w/w to 35% w/w of the entericcoating.
 2. The composition of claim 1, wherein the individualparticulates have an average diameter of 0.5 mm to 1.7 mm, and furthercomprise an enteric coating material and a disintegrant combination thatcause the individual particulates to release at least about 50% of thecannabinoid oil in a subject's duodenum for treating inflammation of theduodenum.
 3. The composition of claim 1, wherein the individualparticulates have an average diameter of 0.5 to 1.7 mm, and areconfigured to release at least about 50% of the cannabinoid oil in ajejunum for treating inflammation of the jejunum.
 4. The composition ofclaim 1, wherein the individual particulates have an average diameter of0.5 to 1.7 mm, and are configured to release at least about 50% of thecannabinoid oil in an ileum for treating inflammation of the ileum. 5.The composition of claim 1, wherein the cannabinoid oil is bound in themicrocrystalline cellulose by being stored within the microcrystallinecellulose's fibrous network.
 6. The composition of claim 1, wherein thecannabinoid oil bound in microcrystalline cellulose is substantiallydry.
 7. The composition of claim 1, wherein the cannabinoid oil includescannabidiol (CBD) oil.
 8. The composition of claim 2, wherein theenteric coating dissolves at a pH between 4 and
 6. 9. The composition ofclaim 3, wherein the enteric coating dissolves at a pH between 5.5 and6.5.
 10. The composition of claim 4, wherein the enteric coatingdissolves at a pH between 6.5 and 7.4.
 11. The composition of claim 8,wherein the enteric coating is methacrylic acid-ethyl acrylatecopolymer.
 12. The composition of claim 9, wherein the enteric coatingis hypromellose acetate succinate.
 13. The composition of claim 10,wherein the enteric coating is methacrylic copolymer with carboxylicacid functional groups.
 14. The composition of claim 1, wherein theindividual particulates further comprise a subcoating between the solidcore and the enteric coating.
 15. The composition of claim 14, whereinthe subcoating is gelatin.
 16. The composition of claim 1, wherein thesolid core further comprises a hydrogel forming polymer.